Histone deacetylases (HDACs) are important zinc hydrolases that are responsible for the regulation of gene expression through deacetylation of the N-acetyl lysine residues of histone proteins and other transcriptional regulators. HDACs are involved in cell-cycle progression and differentiation. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumor effects and can inhibit cell growth, induce terminal termination, and prevent the formation of tumors in mice models.
Evidence from recent studies suggest that transcriptional dysregulation may contribute to the molecular pathogenesis of Huntington's disease (HD). HD is an inherited, progressive neurological disorder that is caused by a CAG/polyglutamine repeat expansion for which there is currently no effective therapy. It has been recently reported that administration of the potent histone deacetylase inhibitor SAHA is effective against Huntington's disease in a mouse model. Orally administered SAHA dramatically improved the motor impairment in mice. HDAC inhibitors, therefore, have the potential to be effective HD therapeutics.
The X-ray structure of an HDAC-like ortholog from the thermophilic bacterium Aquifex aeolicus (Histone Deacetylase-Like Protein (HDLP)—sequence family 3.40.800.20.1-1C3P.pdb) is known. For example, structures of a HDAC homologue bound to the TSA and SAHA inhibitors, have been disclosed by Finnin et al., Science, 401, 188, (1999).
This HDAC-like protein shares a 35% identity with human HDAC1 over 375 residues, deacetylates histones in vitro, and is inhibited by TSA and SAHA. The structure shows an active site containing a zinc-binding site and the residues making up the active site and contact the inhibitors are conserved across the known members of the HDAC family. The HDLP structure, therefore, provides a structural rationale for the design of HDAC inhibitors.
The currently known HDAC inhibitors in the art such as TSA and SAHA may pose limitations with respect to their utility. For example, the polyene chain present in TSA is potentially subject to metabolism. Also, TSA is highly hydrophobic and may be substantially protein bound. The corresponding saturated chain in SAHA is expected to reduce affinity because of entropy considerations in confining the flexible chain to a single conformation when bound in the HDAC site.